7-heterocyclyl quinoline and thieno[2,3-b]pyridine derivatives useful as antagonists of gonadotropin releasing hormone

ABSTRACT

The present invention is directed to novel 7-heterocyclyl quinoline and thieno[2,3-b]pyridine derivatives of the general formula (I) or (II)                    
     wherein all variables are as herein defined, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions associated with gonadotropin releasing hormone (GnRH). The compounds of the invention are antagonists of GnRH, useful in the treatment of the infertility, prostate cancer, benign prostate hyperplasia (BPH) and as contraceptives.

This application is a divisional of parent application Ser. No.09/992,785, filed Nov. 14, 2001 now U.S. Pat. No. 6,583,153. Thisapplication claims the benefit of provisional application No. 60/254,827file on Dec. 12, 2000.

FIELD OF THE INVENTION

The present invention is directed to novel 7-heterocyclyl quinoline andthieno[2,3-b]pyridine derivatives, pharmaceutical compositionscontaining them and their use in the treatment of disorders andconditions associated with gonadotropin releasing hormone (GnRH). Thecompounds of the invention are antagonists of GnRH, useful in thetreatment of infertility, prostate cancer, benign prostate hyperplasia(BPH), and useful as contraceptives.

BACKGROUND OF THE INVENTION

Gonadotropin-releasing hormone (GnRH), also referred to as luteinizinghormone-releasing hormone (LHRH) is a linear decapeptide amide,pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂, originally isolated fromporcine (Matsuo, H., et. al., Biochem. Biophys. Res. Commun. 1972, 43,1334-1339) and ovine (Burgus, R., et. al., PNAS, USA, 1972, 69, 278-282)sources. GnRH plays a key role in the reproductive system. The hormoneis released from the hypothalamus and acts on the pituitary gland tostimulate the biosynthesis and secretion of luteinizing hormone (LH) andfollicle-stimulating hormone (FSH). LH released from the pituitary glandis primarily responsible for the regulation of gonadal steroidproduction in both males and females, whereas FSH regulatesspermatogenesis in males and follicular development in females.

GnRH-based therapies using peptidic GnRH agonists and antagonists havebeen shown effective in the treatment of conditions associated withLH/FSH release, such as endometriosis, uterine fibroids, polycysticovarian disease, precocious puberty and some gonadal steroid-dependentneoplasia, particularly prostate cancer, breast cancer and ovariancancer. GnRH agonists and antagonists are also useful in the treatmentof fertility and as a contraceptive in both males and females.

Although the compounds of the present invention are useful primarily forthe treatment of disorders and conditions associated with thereproductive system, they may also be useful for the treatment of otherGnRH mediated disorders and conditions including pituitary gonadotropeadenomas, sleep disorders, benign prostate hyperplasia, and prostatecancer.

Peptide-like GnRH antagonists are known, for example, derivatives ofstraight-chain peptides (U.S. Pat. Nos. 5,140,009 and 517,835), cyclichexapeptide derivatives (Japanese Patent Application Laid-open No.61(1986)-191698), and bicyclic peptide derivatives (J. Med. Chem. 1993,36, 3265). However, due to a lack of bioavailability, these compoundsare limited to intravenous and subcutaneous administration.

Recently, small molecule, non-peptide GnRH antagonists have beendisclosed. Kato, et al., in EP0679642 disclose isochroman derivativeswhich have gonadotropin releasing hormone receptor antagonizingactivity, as well as calcium-antagonizing and monoamine-uptakeinhibiting activities.

Ohkawa et al., in WO96/38438 disclose tricyclic diazepine derivativeswhich have gonadotropin releasing hormone receptor antagonist activity.

Ohkawa et al., in WO95/29900 disclose condensed heterocyclic compoundswhich have GnRH receptor antagonistic action and/or an action ofimproving sleep disturbances.

Furuya et al., in WO97/14682 disclose quinolone derivatives as GnRHantagonists, useful as prophylactic or therapeutic agents for theprevention or treatment of sex hormone dependent disease.

Goulet et al., in WO97/44037 and in WO97/44041, Goulet et al., inWO97/44321 and Goulet et al., in WO97/44339 disclose non-peptideantagonists of GnRH useful for the treatment of a variety of sex-hormonerelated conditions in men and women. Goulet et al., in WO97/21703 and inWO97/21707 disclose non-peptide antagonists of GnRH useful for thetreatment of a variety of sex-hormone related conditions in men andwomen.

Furuya et al., in WO95/28405 disclose bicyclic thiophene derivativeswith gonadotropin releasing hormone receptor antagonizing activity.Furuya et al., in WO97/41126 disclose4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives having GnRHantagonistic activity. Furuya, et al., in WO97/14697 disclosethieno[2,3-b]pyridine derivatives as GnRH antagonists.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I) or (II):

wherein

L¹ is selected from the group consisting of CH₂, CH(CH₃) and C(CH₃)₂;

R¹ and R²are independently selected from the group consisting of alkyl,cycloalkyl, aryl, aralkyl, heteroaryl and heterocycloalkyl; wherein thearyl, heteroaryl or heterocycloalkyl group is optionally substitutedwith one or more substituents independently selected from halogen,alkyl, alkoxy, nitro, NH₂, NH(alkyl), N(alkyl)₂, —C(O)-alkyl, —C(O)-arylor —C(O)-cycloalkyl;

X is selected from the group consisting of O, S and NR^(A); where R^(A)is selected from hydrogen, alkyl, aryl or aralkyl;

R⁴ is selected from the group consisting of —C(O)—R^(B), —C(O)O—R^(B),—C(O)NH₂, —C(O)—NH^(B), —C(O)—N(R^(B))₂, and —C(O)NHNH₂;

wherein R^(B) is selected from the group consisting of alkyl, aryl,aralkyl and cycloalkyl;

alternatively X is N and is taken together with R⁴ to form a ringstructure selected from the group consisting of pyrazolyl,dihydropyrazolyl, isoxazolinyl and dihydropyrimidinyl; wherein the ringstructure is optionally substituted with one or more R^(C);

wherein each R^(C) is independently selected from the group consistingof oxo, alkyl, alkoxy, amino, alkylamino, dialkylamino, aryl, —O-aryl,aralkyl and —O-aralkyl;

L² is selected from the group consisting of alkyl;

R³ is selected from the group consisting of alkyl, cycloalkyl, aryl,aralkyl, heteroaryl and heterocycloalkyl; wherein the cycloalkyl, aryl,aralkyl, heteroaryl or heterocycloalkyl group is optionally substitutedwith one or more substituents independently selected from halogen,alkyl, alkoxy, nitro, NH₂, NH(alkyl), N(alkyl)₂, cyano or sulfonamido;

R⁵ is selected from the group consisting of halogen, cycloalkyl, aryl,aralkyl, heteroaryl or heterocycloalkyl; wherein the cycloalkyl, aryl,aralkyl, heteroaryl or heterocycloalkyl group is optionally substitutedwith one or more substituents selected from halogen, alkyl, alkoxy,nitro, NH₂, NH(alkyl), N(alkyl)₂, cyano or sulfonamido;

provided that when X is O, then R⁵ is selected from the group consistingof heteroaryl or heterocycloalkyl; wherein the heteroaryl orheterocycloalkyl group is optionally substituted with one or moresubstituents selected from halogen, alkyl, alkoxy, nitro, NH₂,NH(alkyl), N(alkyl)₂, cyano or sulfonamido;

and pharmaceutically acceptable salts, esters and pro-drugs thereof.

In an aspect of the present invention is the compound4,7-dihydro-2-(4-methoxyphenyl)-7-[(2-methoxyphenyl)methyl]-3-[[methyl(phenylmethyl)amino]methyl]-4-oxo-thieno[2,3-b]pyridine-5-carboxylicacid hydrazide, and pharmaceutically acceptable salts, esters andprodrugs thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating disorders or diseaseswhich respond to antagonism of GnRH, in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

An example of the invention is a method for treating infertility,prostate cancer or benign prostate hyperplasia (BPH), in a subject inneed thereof comprising administering to the subject an effective amountof any of the compounds or pharmaceutical compositions described above.

A further example of the invention is a method of female or malecontraception, in a subject in need thereof comprising administering tothe subject a therapeutically effective amount of any of the compoundsor pharmaceutical compositions described above.

Yet another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)infertility, (b) prostate cancer, (c) benign prostate hyperplasia (BPH)or for (d) contraception, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I) or (II):

wherein L¹, R¹, R², X, R⁴, L², R³ and R⁵ are as previously described,useful in the treatment of disorders or diseases which respond toantagonism of the GnRH such as infertility, prostate cancer, benignprostate hyperplasia (BPH), and the like. The compounds of the presentinvention are further useful as contraceptives.

In one embodiment of the present invention are compounds of the formula(I) wherein

L¹ is CH₂;

R¹ and R² are independently selected from the group consisting of loweralkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocycloalkyl;wherein the aryl, aralkyl, heteroaryl or heterocycloalkyl may beoptionally substituted with one to two substituents independentlyselected from halogen, lower alkyl, lower alkoxy, nitro, NH₂, NH(loweralkyl) or N(lower alkyl)₂;

X is O;

R⁴ is selected from the group consisting of —C(O)O-alkyl, —C(O)O-aryland —C(O)NHNH₂;

alternatively X is N and is taken together with R⁴ to form a ringstructure selected from the group consisting of pyrazolyl, pyrazolinyl,dihydropyridyl and dihydropyrimidyl, wherein the ring structure isoptionally substituted with one to two substituents independentlyselected from oxo, lower alkyl, lower alkoxy, aryl, —O-aryl, aralkyl or—O-aralkyl;

L² is selected from the group consisting of lower alkyl;

R³ is selected from the group consisting of aryl; wherein the aryl groupis optionally substituted with one to two substituents independentlyselected from halogen, lower alkyl, lower alkoxy, nitro, NH₂, NH(loweralkyl), N(lower alkyl)₂, cyano or sulfonamido;

R⁵ is selected from the group consisting of halogen, cycloalkyl, aryl,aralkyl, heteroaryl, and heterocycloalkyl wherein the cycloalkyl, aryl,aralkyl, heteroaryl or heterocycloalkyl is optionally substituted withone to two substituents independently selected from halogen, loweralkyl, lower alkoxy, nitro, NH₂, NH(lower alkyl), N(lower alkyl)₂, cyanoor sulfonamido;

provided that when X is O, then R⁵ is selected from the group consistingof heteroaryl or heterocycloalkyl; wherein the heteroaryl orheterocyloalkyl group is optionally substituted with one to twosubstituents selected from halogen, lower alkyl, lower alkoxy, nitro,NH₂, NH(lower alkyl), N(lower alkyl)₂, cyano or sulfonamido;

and pharmaceutically acceptable salts, esters and pro-drugs thereof.

In another embodiment of the present invention are compounds of theformula (I) or (II) wherein X is S and R⁵ is selected from the groupconsisting of heteroaryl or heterocycloalkyl; wherein the heteroaryl orheterocycloalkyl group is optionally substituted with one or moresubstituents selected from halogen, alkyl, alkoxy, nitro, NH₂,NH(alkyl), N(alkyl)₂, cyano or sulfonamido;

In a further embodiment of the present invention are compounds of theformula (I) or (II) wherein X is NR^(A) or alternatively X is N and istaken together with R⁴ to form a ring structure selected from the groupconsisting of pyrazolyl, dihydropyrazolyl, isoxazolinyl anddihydropyrimidinyl; wherein the ring structure is optionally substitutedwith one or more R^(C), wherein R^(C) is as defined above.

In a particularly preferred embodiment of the present invention arecompounds of the formula (I) and (II) as listed in Tables 1 and 2.

TABLE I

Mol. Wt. ID # X R⁴ R⁵ (M⁺¹) 1 O —C(O)OCH₂CH₃ 3-thienyl 559 2 O—C(O)OCH₂CH₃ 2-benzofuryl 593 3

bromo 524 4

2-benzofuryl 561 5

2-benzofuryl 651 6

2-benzofuryl 589

TABLE II

Mol Wt ID # X R⁴ (M⁺¹) 7 O —C(O)—NH—NH₂ 569 8

551

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, includes straight and branched chains comprising oneto ten carbon atoms. For example, alkyl radicals include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and thelike. Unless otherwise noted, “lower” when used with alkyl means acarbon chain composition of 1-6 carbon atoms.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like. Unless otherwise noted, “lower” when used withalkoxy means an oxygen ether radical of the above described straight orbranched carbon chain alkyl group wherein the alkyl is of 1-6 carbonatoms.

As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, and the like.

As used herein, unless otherwise noted, “aralkyl” shall mean any loweralkyl group substituted with an aryl group such as phenyl, naphthyl andthe like. For example, benzyl, phenylethyl, phenylpropyl,naphthylmethyl, and the like.

As used herein, unless otherwise noted, “cycloalkyl” shall mean anythree to eight membered, monocyclic, saturated, carbocyclic ringstructure including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cylcooctyl.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated, partially unsaturated or partiallyaromatic ring structure containing at least one heteroatom selected fromthe group consisting of O, N and S, optionally containing one to threeadditional heteroatoms independently selected from the group consistingof O, N and S; or a nine to ten membered saturated, partiallyunsaturated or partially aromatic bicyclic ring system containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to four additional heteroatoms independentlyselected from the group consisting of O, N and S. The heterocycloalkylgroup may be attached at any heteroatom or carbon atom of the ring suchthat the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl and 2,3-dihydrobenzofuryland the like.

When a particular group is “substituted” (e.g., cycloalkyl, aryl,aralkyl, heterocycloalkyl, heteroaryl), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylalkylaminocarbonylalkyl” substituent refersto a group of the formula

Names for chemical entities of the present invention may be generatedusing nomenclature rules known in the art or may alternatively begenerated using commercial chemical naming software, for exampleACD/Index Name (Advanced Chemistry Development, Inc., Toronto, Ontario)

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methyinitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

αMEM=Minimum Essential Medium

DCM=Dichloromethane

DIPEA=Diisopropylethylamine

DMF=N,N-Dimethylformamide

DME=Dimethoxyethane

DMSO=Dimethylsulfoxide

Et₃N=Triethylamine

EtOAc=Ethyl Acetate

LHMDS=Lithium hexamethyldisilazide

MeOH=Methanol

NBS=1-bromo-2,5-pyrrolidinedione

Ph=Phenyl

RT or rt=Room temperature

TEA=Triethylamine

THF=Tetrahydrofuran

Compounds of the general formula (I) wherein X is O, may be preparedaccording to the process outlined in Scheme 1.

More particularly, a compound of formula (III), a known compound orcompound prepared by known methods, wherein Q is bromo or iodo, isreacted with a suitably substituted compound of formula (IV), in thepresence of a base such as potassium carbonate, TEA, NaOH, NaH, DIPEA,and the like, in an organic solvent such as THF, DMF, DCM, and the like,to yield the corresponding compound of formula (V).

The compound of formula (V) is reacted with a brominating agent such as70% NBS, and the like, in an organic solvent such as THF, DMF, DCM, andthe like, to yield the corresponding compound of formula (VI).

The compound of formula (VI) is reacted with a suitably substitutedamine of formula (VII), in the presence of a base such as TEA, DIPEA,and the like, in an organic solvent such as THF, DMF, and the like, toyield the corresponding compound of formula (VIII).

The compound of formula (VIII) is reacted with a suitably substitutedboronic acid of formula (IX), in the presence of a catalyst such aspalladium tetrakis(triphenylphosphine) (Pd(PPh₃)₄), and the like, in thepresence of a base such as NaCO₃, NaOH, and the like, in an organicsolvent such as THF, DMF, dioxane, and the like, optionally in a mixturewith water, to yield the corresponding compound of formula (Ia).

Compounds of formula (I) wherein X is S may be prepared according to theprocess outlined in Scheme 2.

Specifically, a suitably substituted compound of formula (Ia), preparedas in Scheme 1, is reacted with a sulfonating agent such as P₄S₁₀,Lawesson's reagent, and the like, in an organic solvent such aspyridine, toluene, xylene, and the like, at an elevated temperature inthe range of about 60-140° C., to yield the corresponding compound offormula (Ib).

Compounds of formula (I) wherein X is N and is taken together with R⁴ toform

wherein R^(D) is selected from the group consisting of alkyl, aryl andaralkyl, may be prepared according to the process outlined in Scheme 3.

More particularly, a suitably substituted compound of formula (Ib),prepared as in Scheme 2, is reacted with a compound of formula (X), inan organic solvent such as DMF, DMSO, and the like, at an elevatedtemperature in the range of about 80-110°C., to yield the correspondingcompound of formula (Ic).

The compound of formula (Ic) is optionally further reacted with acompound of formula (XI), wherein R^(D) is selected from the groupconsisting of alkyl, aryl and aralkyl, in the presence of a strong basesuch as LHMDS, NaH, potassium t-butoxide, and the like, to yield thecorresponding compound of formula (Id).

Alternatively, the compound of formula (Ic) may be further reactedaccording to known methods to introduce one or more substituents on thepyrazolyl group.

Compounds of formula (I) wherein X is NR^(A) may be prepared accordingto the process outlined in Scheme 4.

More particularly, a suitably substituted compound of formula (Ib),prepared as in Scheme 2, is reacted with a suitably substituted amine offormula (XII), in an organic solvent such as DMF, DMSO, and the like,preferably at an elevated temperature in the range of about 60-120° C.,to yield the corresponding compound of formula (Ie).

Compounds of formula (I) wherein X is N and is taken together with R⁴ toform a ring structure selected from the group consisting ofdihydropyrazolyl, isoxazolinyl and dihydropyrimidinyl may be prepared bymethods known to those skilled in the art.

For example, compounds of formula (I) wherein X is N and is takentogether with R⁴ to form dihydropyrazolyl

may be prepared by reacting a suitably substituted compound of formula(Ia), wherein X is O and R⁴ is an ester of the formula —CO₂R^(B),prepared as in Scheme 1, with a suitable reducing agent, to yield thecorresponding compound wherein R⁴ is an aldehyde of the formula —C(O)H,subsequently reacting the R⁴ aldehyde with benzylcarbazate to yield thecorresponding compound wherein R⁴ is hydrazone (—CHNNH—C(O)O-benzyl),reducing the R⁴ hydrazone with hydrogen gas, in the presence of acatalyst such as palladium hydroxide, to yield the correspondingcompound wherein R⁴ is hydrazine (—CH₂NHNH₂), and then treating the R⁴hydrazine with a dehydration reagent such as P₂O₅, at an elevatedtemperature to yield the corresponding dihydropyrazole substitutedcompound of formula (I).

Compounds of formula (I) wherein X is N and is taken together with R⁴ toform isoxazolinyl

may be prepared by subjecting a suitably substituted compound of formula(Ia), wherein X is O and R⁴ is an ester of the formula —CO₂R^(B),prepared as in Scheme 1, to saponification to convert the R⁴ ester groupto the corresponding carboxy group (—CO₂H) and then treating the R⁴carboxy group with a suitable reducing agent, to yield the correspondingcompound wherein R⁴ is an alcohol of the formula —CH₂OH, converting theX is O carbonyl group to the corresponding X is S thiocarbonyl group,converting the thiocarbonyl group to the corresponding hydroxyaminewhere X is N—OH, and then affecting ring closure of the X hydroxyamineand R⁴ alcohol with a dehydrating agent such as P₂O₅, at an elevatedtemperature to yield the corresponding isoxazolinyl substituted compoundof formula (I).

Compounds of formula (I) wherein X is N and is taken together with R⁴ toform dihydropyrimidinyl

or oxo-substituted dihydropyrimidinyl

may be prepared by reacting a suitably substituted compound of formula(Ia), wherein R⁴ is an ester of the formula —CO₂R^(B), prepared as inScheme 1, with urea, thiourea, guanidine or a suitably subtituted alkylor aryl amidine, in an organic solvent, at an elevated temperature toyield the

substituted compound of formula (I). The oxo-substituteddihydropyrimidinyl substituted compound of formula (I) may be furtheroptionally, alkylated according to the process described in Scheme 3, toyield the corresponding dihydropyrimidinyl substituted compound offormula (I). Similarly, the thio- or imino-substituteddihydropyrimidinyl substituted compound of formula (I) may be further,optionally reacted according to known methods to displace the thio group(═S) or modify the imino group (═NH), respectively.

Compounds of formula (II), wherein R⁴ is —C(O)O—R⁶, X is S or X is N andis taken together with R⁴ to form

may be prepared according to the process outlined in Scheme 5.

More particularly, a compound of formula (X), a known compound orcompound prepared by known methods, is reacted with a sulfonating agentsuch as P₄S₁₀, Lawesson's Reagent, and the like, in the presence of anorganic base such as pyridine, TEA, Hünig's base (DIEA), and the like,at an elevated temperature in the range of about 60-120° C., preferablyat about reflux temperature, to yield the corresponding compound offormula (IIa).

The compound of formula (IIa) may be optionally further reacted withH₂N—NH₂, in an organic solvent such as DMF, DMSO, and the like, at anelevated temperature in the range of about 80-110° C., to yield thecorresponding compound of formula (IIb).

The compound of formula (IIb) may be further, optionally reactedaccording to known methods to introduce one or more substituents on thepyrazolyl group.

Compounds of formula (II) wherein X is N and taken together with R⁴ toform a ring selected from the group consisting of dihydropyrazolyl,isoxazolinyl and dihydropyrimidinyl, may be similarly prepared accordingto the processes described above, with appropriate substitution of acompound of formula (X) for the compound of formula (Ia).

Compounds of formula (II) wherein X is selected from the groupconsisting of O, S and NR^(A), may be prepared from the correspondingcompound of formula (X), by methods known to those skilled in the art.

For example, compounds of formula (II) wherein X is O and R⁴ is otherthan —C(O)OR⁶ may be prepared by converting the R⁴ ester group on asuitably substituted compound of formula (X) to the corresponding R⁴carboxy group and then using known quinolone chemistry to convert the R⁴carboxy group to the desired R⁴ functionality.

Compounds of formula (II) wherein X is S and R⁴ is other than —C(O)OR⁶,may similarly be prepared by converting the —C(O)OR⁶ ester on thecompound of formula (X) to the desired R⁴ group as described above andthen converting the X is O, (carbonyl group) to the corresponding X is S(thiocarbonyl group) by reacting with a sulfonating agent, as describedin Scheme 5.

Compounds of formula (II) wherein X is NR^(A) and R⁴ is other than—C(O)OR⁶, may similarly be prepared by converting the —C(O)OR⁶ ester onthe compound of formula (X) to the desired R⁴ group as described aboveand then converting the X is O (carbonyl group) to the corresponding Xis NR^(A) (amine group) by reacting with a suitably substituted amine,as described in Scheme 4.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLE 17-Bromo-6-bromomethyl-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid Ethylester

A mixture of7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-6-methyl-4-oxoquinoline-3-carboxylicacid ethyl ester (3.5 g, 8 mmol), prepared according to the procedureoutlined in PCT application WO97/14682, Reference Example 3, NBS (1.5 g,8.4 mmol) and 2,2′-azobisisobutyronitrile (AIBN, 100 mg) in DCM (200 mL)was stirred at reflux for 4 h. Additional NBS (750 mg) was added and themixture was refluxed for 4 h. Column chromatography (hexanes:ethylacetate=3:7) yielded the product as a white solid.

Yield: 2.95 g (72%); m.p. 184-187° C.; ¹H NMR (CDCl₃), δ 1.41 (t, J=8Hz, 3H), 4.40 (q, J=8 Hz, 2H), 4.66 (s, 2H), 5.36 (s, 2H), 7.03 (m, 2H),7.39 (m, 1H), 7.92 (s, 1H), 8.54 (s, 1H), 8.68 (ds, 1H); MS (m/z): 514(MH⁺).

EXAMPLE 26-(N-Benzyl-N-methylaminomethyl)-7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid Ethylester

A mixture of7-bromo-6-bromomethyl-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ethyl ester (110 mg, 0.21 mmol), methylbenzylamine (31 mg, 0.26mmol) in DIPEA (0.045 mL) and DMF (15 mL) was stirred at roomtemperature for 16 h. Ethyl acetate and water were added. The organicphase was separated and washed with water, dried with MgSO₄. The solventwas evaporated and the residue dried under vacuum to yield the productas a white solid.

Yield: 120 mg (100%); ¹H NMR (CDCl₃), δ 1.41 (t, J=8 Hz, 3H), 2.17 (s,3H), 3.62 (s, 2H), 3.67 (s, 2H), 4.40 (q, J=8 Hz, 2H), 5.36 (s, 2H),7.03 (m, 2H), 7.25-7.39 (m, 6H), 7.88 (s, 1H), 8.59 (s, 1H), 8.67 (ds,1H); MS (m/z): 555 (MH⁺).

EXAMPLE 36-(N-Benzyl-N-methylaminomethyl)-7-(benzofuran-2-yl)-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid Ethylester Compound #2

A mixture of7-bromo-6-bromomethyl-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ethyl ester (278 mg, 0.5 mmol), benzofuran-2-boronic acid (97 mg,0.6 mmol), tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.06 mmol)and 2M sodium carbonate (414 mg, 3 mmol) in DME (20 mL) was heated atreflux for 16 h. Ethyl acetate and water were added. The organic phasewas separated and washed with water and dried with MgSO₄. Columnchromatography (ethyl acetate) yielded the product as a yellow solid.

Yield: 55 mg (19%); ¹H NMR (CDCl₃), δ 1.44 (t, J=8 Hz, 3H), 2.17 (s,3H), 3.63 (s, 2H), 3.90 (s, 2H), 4.42 (q, J=8 Hz, 2H), 5.49 (s, 2H),7.00 (m, 2H), 7.22-7.81 (m, 11H), 8.23 (s, 1H), 8.62 (s, 1H), 8.76 (ds,1H); MS (m/z): 593 (MH⁺).

EXAMPLE 42,5-Dihydro-7-(4-methoxyphenyl)-5-[(2-methoxyphenyl)methyl]-8-[[methyl(phenylmethyl)amino]methyl]-3H-pyrazolo[3,4-d]thieno[2,3-b]pyridin-3-oneCompound #8

To a solution of4,7-dihydro-2-(4-methoxy-phenyl)-7-[(2-methoxyphenyl)methyl]-3-[[methyl(phenylmethyl)amino]methyl]-4-oxo-thieno[2,3-b]pyridine-5-carboxylicacid, ethyl ester (prepared according to the procedure described byFuruya, S, et al., in PCT Application WO95/28405), (387 mg, 0.66 mmol)in pyridine (3 mL) was added P₄S₁₀. The reaction flask was flushed withargon and stirred at reflux for 5 hours. The solvent was removed and theproduct purified by flash chromatography to yield the correspondingthiocarbonyl.

The thiocarbonyl (118 mg, 0.19 mmol) was dissolved in dry DMF (0.25 mL)and treated with hydrazine monohydrate (0.02 mL, 0.42 mmol). Theresulting solution was heated to 80° C. for 2 hours, the mixture wascooled and purified by flash chromatography (0-10% MeOH/CHCl₃). Theproduct was converted to its hydrochloride salt by treating with HCl toyield the product as a yellow powder.

Yield: 7.5 mg; MS (m/z) 551 (MH⁺).

EXAMPLE 52,5-Dihydro-7-(benzofuran-2-yl)-8-[[methyl(phenylmethyl)amino]methyl]-5-[(2,6-difluorophenyl)methyl]-3H-pyrazolo[4,3-c]quinolin-3-oneCompound #4

To a solution of7-(benzofuran-2-yl)-8-[[methyl(phenylmethyl)-amino]-methyl]-5-[(2,6-difluorophenyl)methyl]-3-quinolinecarboxylicacid ethyl ester, (500 mg, 0.84 mmol) in pyridine (5 mL) was added P₄S₁₀(240 mg, 0.65 eq). The reaction flask was flushed with argon and stirredat reflux for 2 hours, cooled to 100° C. and poured into water (100 mL).The product was extracted into chloroform, dried (MgSO₄) andconcentrated to yield a red-brown solid.

The solid (337 mg, 0.55 mmol) was dissolved in dry DMF (5 mL) andtreated with hydrazine monohydrate (60 mg, 1.1 mmol). The resultingmixture was warmed to 100° C. for 3 hours, the mixture was cooled andpoured onto water. The resulting yellow precipitate was collected byfiltration and dried to yield the product.

Yield: 149 mg; ¹H NMR (CDCl₃) δ 2.09 (s, 3H), 3.57 (s, 2H), 3.86 (s,2H), 5.84 (s, 2H), 7.18-7.49 (m, 12H), 7.66-7.77 (m, 2H), 8.16 (s, 1H),8.33 (s, 1H), 8.95 (s, 1H).

EXAMPLE 67-(Benzofuran-2-yl)-3-[(phenylmethyl)oxy]-5-[(2,6-difluorophenyl)methyl]-8-[[methyl(phenylmethyl)amino]methyl]-5H-pyrazolo[4,3-c]quinolineCompound #5

A solution of2,5-dihydro-7-(benzofuran-2-yl)-8-[[methyl(phenylmethyl)amino]methyl]-5-[(2,6-difluorophenyl)methyl]-3H-pyrazolo[4,3-c]quinolin-3-one(120 mg, 0.21 mmol) in dry DMF (5 mL) was treated with a solution oflithium hexamethyidisilazide (0.25 mL, 0.25 mol, 1.0 M) intetrahydrofuran (THF). Benzyl bromide (40 mg, 0.22 mmol) was introducedvia syringe and the mixture was stirred overnight. One equivalenthydrochloric acid in ether was added and the solvent evaporated to yieldthe corresponding hydrochloride salt product as a yellow solid.

Yield: 47 mg; ¹H NMR (CDCl₃) δ 2.08 (s, 3H), 3.55 (s, 2H), 3.87 (s, 2H),5.13 (s, 2H), 5.88 (s, 2H), 7.12-7.51 (m, 16H), 7.66-7.70 (m, 2H), 8.16(s, 1H), 8.37 (s, 1H), 9.10 (s, 1H).

EXAMPLE 76-(N-Benzyl-N-methylaminomethyl)-7-(thien-3-yl)-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid Ethyl Ester Compound #1

Following the procedure described in Example 3, the compound prepared inExample 2(6-(N-Benzyl-N-methylaminomethyl)-7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ethylester) (150 mg, 0.27 mmol) was reacted withthiophene-3-boronic acid (38.4 mg, 0.30 mmol), to yield the product as ayellow solid.

Yield: 48 mg; MS (m/z) 559 (MH⁺).

EXAMPLE 82,5-Dihydro-7-bromo-8-[[methyl(phenylmethyl)amino]methyl]-5-[(2,6-difluorophenyl)methyl]-3H-pyrazolo[4,3-c]quinolin-3-oneCompound #3

Following the procedure described in Example 4,6-(N-benzyl-N-methylaminomethyl)-7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ethyl ester (0.6 g, 1.1 mmol) was converted to the title compoundand isolated as the corresponding hydrochloride salt, as a yellowpowder.

Yield: 0.15 g; MS (m/z) 524 (MH⁺).

EXAMPLE 97-(Benzofuran-2-yl)-3-ethoxy-5-[(2,6-difluorophenyl)methyl]-8-[[methyl(phenylmethyl)amino]methyl]-5H-pyrazolo[4,3-c]quinolineHCl Compound #6

Following the procedure described in Example 6,2,5-dihydro-7-(benzofuran-2-yl)-8-[[methyl(phenylmethyl)amino]methyl]-5-[(2,6-difluorophenyl)methyl]-3H-pyrazolo[4,3-c]quinolin-3-one(0.05 g, 0.09 mmol) was reacted with ethyl iodide (0.018 g, 0.116 mmol)to yield the title compound, which was isolated as its correspondinghydrochloride salt, as a yellow powder.

Yield: 0.05 g; MS (m/z) 589 (MH⁺).

EXAMPLE 104,7-Dihydro-2-(4-methoxyphenyl)-7-[(2-methoxyphenyl)methyl]-3-[[methyl(phenylmethyl)amino]methyl]-4-oxo-thieno[2,3-b]pyridine-5-carboxylicAcid, Hydrazide bis-Hydrochloride Compound #7

To a solution of4,7-dibydro-2-(4-methoxyphenyl)-7-[(2-methoxyphenyl)methyl]-3-[[methyl(phenylmethyl)amino]methyl]-4-oxo-thieno[2,3-b]pyridine-5-carboxylicacid, ethyl ester (57 mg, 0.097 mmol) in ethyl alcohol (2 mL) was addedhydrazine (0.030 mL, 0.096 mmol). The mixture was heated to reflux for 6hours and concentrated in vacuo. Trituration of the residue with diethylether and collection of the solid by precipitation yielded the productas a pale yellow solid.

Yield: 38 mg; MS (m/z) 569 (MH⁺).

EXAMPLE 11 GnRH Receptor Binding Assay

A homogenate prepared from an equal mixture of female and male ratpituitaries was used as the source of the membrane-bound GnRH receptor.The receptor was allowed to interact in solution with [¹²⁵I]-histrelinalone or in combination with a competitive ligand (the compound beingtested). The bound radiolabeled ligand was separated from the free(unbound) radiolabeled ligand by filtration through glass filter matsusing a 96-well plate harvesting system (Tomtec Mach II 96). In theabsence of a competitive ligand, a maximum amount of radiolabeled ligandis bound to the receptor and trapped by the glass filter mats. When anunlabelled ligand that can compete for the receptor site is present, theamount of radiolabeled ligand bound to the receptor and trapped on thefilter mat is proportionally reduced depending on the concentration ofthe competitor and on the strength of the competitor's affinity for thereceptor. The amount of receptor-bound [¹²⁵I]-histrelin on the filtermat was determined using a Wallac Betaplate™ Liquid ScintillationCounter. Binding was determined as follows:

NSB Non-specific binding

B₀ maximum concentration of compound

Average NSB: (NSB1+NSB2)/2

Average B₀: (B₀1+B₀2)/2

Corrected B₀: Average B₀−Average NSB

% inhibition of Corrected B₀ (or maximum response) was calculated asfollows:

% Inhibition=100−[((Actual counts per minute−Average NSB)/CorrectedB₀)*100]

EXAMPLE 12 LUCIFERASE Assay for GnRH

Hek 293 cells with the GnRHR gene were transfected with the hCG promoterand the luciferase reporter system. On day 1, the cells were plated at adensity of 80,000 cells per well on a Poly-D-lysine pre-coated 96 wellplate. The plates were incubated at 37° C. for 24 hours. On day 2, thespent media was decanted and replaced with fresh media. Test compounds,standard and controls were added to individual wells. All the dilutionswere done in 7.5% DMSO/(αMEM media. The assay was run in both agonistand antagonist format. For the antagonist format, the assay measurementswere run against a standard of 0.6 nM Histrelin. On day 3, the levels ofluciferase production were measured in a chemiluminescence assay usingEnhanced Luciferase Assay Kit. The results were expressed as %Inhibition using the following formula:

RLU Relative Light Units, a measure of chemiluminescence

Agonist [RLU value(test compound)−(Background/0.6 nMHistrelin)−Background]*100

Antagonist (1−[(RLU value−(Background/0.6 nMHistrelin)−Background)*100])

The calculated percentages were plotted on a graph using Graph Pad Prizmand the IC₅₀/EC₅₀ values determined.

EXAMPLE 13 Primary Pituitary Cell Culture Assay

Male rats (between immature and adult) were sacrificed and the anteriorpituitaries were collected from them. The pituitaries were dissociatedand the cells were plated at a concentration of 0.33×10⁶ cells/well onday 1. On day 3 the media on the cells was flushed and replaced withfresh media. The test compound was then added to the plated cells at aconcentration ranging from 1 nM to 1000 nM. The plates were incubated at37° C. at 5% CO₂ for 2 days. On Day 5 the media was flushed again andreplaced with fresh media. To the plates were then added test compoundand 1 nM GnRH. The cells were incubated for 4 hours, the media wascollected by centrifuging the plates at 1200 rpm Sorvall RT7 for 10minutes, 900 μL of supernatant was pipetted from each well and dispensedto a 96 well plate. The deep well plates were covered and stored at 20°C. for a day. The plates are then evaluated by ELISA (a radioimmunoassaysystem) to determine the concentration of lutenizing hormone in themedia. The assay was repeated at varying concentrations of the testcompounds to determine IC₅₀ values. The IC₅₀ value is defined as theconcentration of test compound at which 50% inhibition was achieved.

Following the procedures set forth above, selected compounds of thepresent invention were tested, with results as listed in Table 3.

TABLE 3 Biological Activity ID Binding, IC₅₀ Luciferase Assay PituitaryCell # (B % @ 30 μM) IC₅₀ (μM) Assay IC₅₀ (μM) 1 32 μM 10 (antagonist) 2— 3.26 (antagonist) 2.43 3 16 4  1 5  5 6  5 7  1.6 1.48 8 30

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. A compound of the formula (II)

wherein L¹ is selected from the group consisting of CH₂, CH(CH₃) andC(CH₃)₂; R¹ and R² are independently selected from the group consistingof alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocycloalkyl;wherein the aryl, heteroaryl or heterocycloalkyl group is optionallysubstituted with one or more substituents independently selected fromhalogen, alkyl, alkoxy, nitro, NH₂, NH(alkyl), N(alkyl)₂, —C(O)-alkyl,—C(O)-aryl or —C(O)-cycloalkyl; X is selected from the group consistingof O, S and NR^(A); where R^(A) is selected from hydrogen, alkyl, arylor aralkyl; R⁴ is selected from the group consisting of —C(O)—R^(B),—C(O)O—R^(B), —C(O)NH₂, —C(O)—NHR^(B), —C(O)—N(R^(B))₂, and —C(O)NHNH₂;wherein R^(B) is selected from the group consisting of alkyl, aryl,aralkyl and cycloalkyl; alternatively X is N and is taken together withR⁴ to form a ring structure selected from the group consisting ofpyrazolyl, dihydropyrazolyl, isoxazolinyl and dihydropyrimidinyl;wherein the ring structure is optionally substituted with one or moreR^(C); wherein each R^(C) is independently selected from the groupconsisting of oxo, alkyl, alkoxy, amino, alkylamino, dialkylamino, aryl,—O-aryl, aralkyl and —O-aralkyl; L² is selected from the groupconsisting of alkyl; R³ is selected from the group consisting of alkyl,cycloalkyl, aryl, aralkyl, heteroaryl and heterocycloalkyl; wherein thecycloalkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, alkyl, alkoxy, nitro, NH₂, NH(alkyl), N(alkyl)₂,cyano or sulfonamido; R⁵ is selected from the group consisting ofhalogen, cycloalkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl;wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heterocycloalkylgroup is optionally substituted with one or more substituents selectedfrom halogen, alkyl, alkoxy, nitro, NH₂, NH(alkyl), N(alkyl)₂, cyano orsulfonamido; provided that when X is O, then R⁵ is selected from thegroup consisting of heteroaryl or heterocycloalkyl; wherein theheteroaryl or heterocycloalkyl group is optionally substituted with oneor more substituents selected from halogen, alkyl, alkoxy, nitro, NH₂,NH(alkyl), N(alkyl)₂, cyano or sulfonamido; or a pharmaceuticallyacceptable salt, ester or pro-drug thereof.
 2. A compound as in claim 1wherein X is NR^(A) or X is N and is taken together with R⁴ to form aring structure selected from the group consisting of pyrazolyl,dihydropyrazolyl, isoxazolinyl and dihydropyrimidinyl; wherein the ringstructure is optionally substituted with one or more R^(C); wherein eachR^(C) is independently selected from selected the group consisting ofoxo, alkyl, alkoxy, amino, alkylamino, dialkylamino, aryl, —O-aryl,aralkyl and —O-aralkyl; or a pharmaceutically acceptable salt, ester orpro-drug thereof.
 3. A compound as in claim 1 identified as2,5-dihydro-7-(4-methoxyphenyl)-5-[(2-methoxyphenyl)methyl]-8-[[methyl(phenylmethyl)amino]methyl]-3H-pyrazolo[3,4-d]thieno[2,3-b]pyridin-3-one;or a pharmaceutically acceptable salt, ester or pro-drug thereof.
 4. Acompound identified as4,7-dihydro-2-(4-methoxyphenyl)-7-[(2-methoxyphenyl)methyl]-3-[[methyl(phenylmethyl)amino]methyl]-4-oxo-thieno[2,3-b]pyridine-5-carboxylicacid hydrazide, or a pharmaceutically acceptable salt, ester or prodrugthereof.
 5. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 6. A process for making apharmaceutical composition comprising mixing a compound of claim 1 and apharmaceutically acceptable carrier.
 7. A method of treating a disorderor disease which respond to antagonism of the GnRH in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of the composition of claim 5 wherein the disorder ordisease is selected from the group consisting of infertility, prostatecancer and benign prostate hyperplasia (BPH).
 8. A method ofcontraception in a subject in need thereof comprising administering tothe subject a therapeutically effective amount of the compound ofclaim
 1. 9. A method of treating a condition selected from the groupconsisting of the infertility, prostate cancer and benign prostatehyperplasia (BPH) in a subject in need thereof comprising administeringto the subject a therapeutically effective amount of the compound ofclaim
 1. 10. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a compound of claim
 4. 11. A process for making apharmaceutical composition comprising mixing a compound of claim 4 and apharmaceutically acceptable carrier.
 12. A method of treating a disorderor disease which respond to antagonism of the GnRH in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of the composition of claim 10 wherein the disorder ordisease is selected from the group consisting of infertility, prostatecancer and benign prostate hyperplasia (BPH).
 13. A method ofcontraception in a subject in need thereof comprising administering tothe subject a therapeutically effective amount of the compound of claim4.
 14. A method of treating a condition selected from the groupconsisting of the infertility, prostate cancer and benign prostatehyperplasia (BPH) in a subject in need thereof comprising administeringto the subject a therapeutically effective amount of the compound ofclaim 4.